1. Field of the Invention
The present invention generally applies to the treatment of ocular conditions, and specifically applies to improved methods, materials and devices for the non-invasive treatment of intermediate and posterior eye pathologies.
2. Background Art
Numerous sight-threatening maladies result from diseases in the posterior portion of the eye. Posterior and intermediate uveitis, HSV retinitis, age related macular degeneration, diabetic retinopathy, bacterial, fungal, or viral endophthalmitis, eye cancers, glioblastomas, and glaucomatous degradation of the optic nerve are but a few of the diseases that will result in blindness if left untreated.
A plethora of conventional pharmacological agents currently exist to treat these conditions. Delivery of the agents to the site of action, however, has heretofore proven difficult. In order to exert a sufficient pharmaceutical effect on the intermediate and posterior eye tissues, the compound must be delivered to these tissues in pharmacologically relevant concentrations. Delivering therapeutic concentration of drug to the intermediate and posterior ocular region via conventional delivery methods has proven difficult in practice, as the methods are fraught with drawbacks.
Currently, there are four known methods of delivering the compounds to the posterior ocular chamber including: direct injection into the vitreous, systemic administration with subsequent distribution into the eye through optic blood flow, injection into the areas surrounding the globe with subsequent passive diffusion through the sclera into the globe, and topical application to the cornea and/or sclera with subsequent passive diffusion posteriorly into the globe's interior. Each of the above-mentioned methods has its shortcomings.
The preferred delivery method for drug administration into any body tissue is by oral administration due to its simplicity, non-invasiveness, and patient acceptance. Less acceptable, but effective methods of reaching body tissues by way of the systemic vasculature include invasive transcutaneous injections of compounds through the skin. Yet other methods involve non-invasive transport by percutaneous absorption. Generally, however, delivery of a drug into the eye via systemic methods is difficult because the eye is an immunoprivileged organ. The blood vessels supplying the eye have tight junctions between their endothelial cells, thus preventing the transfer of most non-endogenous compounds from the blood to the eye. In this way, the blood-retinal barrier's function is very similar to the protection afforded the central nervous system by the blood-brain barrier. The blood-retinal barrier inhibits entry of most systemically circulating drugs into the eye itself. In order to achieve therapeutic concentrations in the eye following systemic delivery, therefore, large quantities of the drug must be administered to overcome the barrier. The excessive quantities of the drug in the systemic circulation, of course, expose the entire body to the negative effects and potential toxicity of the drugs. For example, if a steroid is administered in large doses to a patient, such as for the treatment of uveitis, the entire body experiences the steroidal effects. These effects include fluid retention, electrolyte imbalance, immunosuppression, myopathy, cataract formation, behavior changes and bone demineralization, among others. Similarly, if large doses of a vascular endothelial growth factor (VEGF) antagonist are administered, systemic effects include the delayed healing of injuries and decreased blood perfusion to body tissues. As such, whole body toxicity precludes systemic delivery of medicaments as a way to achieve therapeutic concentration in the globe's interior.
More targeted, non-systemic delivery methods are similarly known in the art. As early as the 1920's, clinicians administered drugs to the eye by retrobulbar injection. Other methods have developed through the years, including sub-tenon's capsule, peribulbar, and subconjunctival injections, all of which comprise invasive delivery methods for injecting large amounts of a drug into a periocular space. Through injection to areas surrounding the globe, these methods achieve a high local concentration of the drug, allowing for transcleral drug delivery to the posterior chamber by passive, Fickian driven diffusion. The injections, however, carry significant risks, including pain, risk of infection, tissue scarring, retrobulbar hemorrhage, ecchymosis, elevated intraocular pressure, accidental perforation of the globe, and eye proptosis. Further, despite their relatively targeted nature, periocular injections can result in high systemic drug concentrations because the drug does not diffuse unidirectionally into the globe, but diffuses radially into the capillaries and vasculature surrounding the globe. In fact, some researchers found systemic levels of 60 ng/ml plasma following a 5 mg peribulbar injection of dexamethasone; a plasma concentration they concluded was comparable to a “high oral dose” (approximately 7.5 mg). Weijtens O, Van Der Sluijs F A, Schoemaker R C, Lentjes EGWM, Choen A F, Romijn FPHTM, and Van Meurs J C (1997). Peribulbar corticosteroid injection: vitreal and serum concentrations after dexamethasone disodium phosphate injection. Am J Ophthalmol, 123:358-63.
Another method for the introduction of medicament into the eye includes direct injection of the drug into the vitreous. Intravitreal injections have been used to deliver antibacterial and antifungal agents for the treatment of bacterial and fungal endophthalmitis, antivirals for treatment of viral retinitis, and steroids for the treatment of uveitis. The half-life of most compounds in the vitreous, however, is relatively short, usually on the scale of just a few hours. Therefore, the intravitreal injections must be repeated, often multiple times a week. The repeated injections can cause pain, discomfort, intraocular pressure increases, intraocular bleeding, increased chances for infection, and the possibility of retinal detachment.
A similar method to the intravitreal injections requires the implantation of drug containment matrices into the vitreal compartment or the surgical implantation of a sustained release drug delivery device into the vitreal compartment. Such devices may be bioerodible, or non-erodible. They often must be, however, surgically implanted into the interior of the globe to be effective. Once the drug payload is exhausted, a new matrix may be inserted to replace the old, or the old device left in place and a new matrix inserted nearby. Although effective, such devices carry with them significant risks, separate and apart from the risks associated with major implantation surgery. The problems include pain, discomfort, intraocular bleeding, intraocular pressure increases, chance of infection, and the possibility of retinal detachment. Lastly, if ocular drug toxicity is observed, such as increased intraocular pressure or cataractogenesis during implantation therapy, the toxicity has to be managed or the device removed.
One final category of drug delivery includes the introduction of materials into the interior of the ocular globe by diffusion through the sclera into the globe's interior. Such diffusion can be passive or active, wherein drug may be driven by an external driving force, such as iontophoresis, into the eye.
For passive delivery of drugs to the eye, a sustained release drug delivery device, a matrix saturated with the drug, a polymer containing the drug, or a collagen shield containing the drug can all be placed adjacent to the episclera. The drug, once in contact with the eye, diffuses into the ocular tissue by a process that is governed by Fick's law. Fick's law reads:J=PAΔC 
Where                J=drug flux into the eye        P=permeability of drug through the sclera        A=area of device in contact with the eye        ΔC=concentration gradient across the sclera        
Despite the well-known nature of Fickian transport, it has not as of yet been recognized that passive delivery through the conjunctiva and sclera could yield therapeutic concentrations of medicament in the posterior portion of the eye. The inability to deliver effective amounts of drug to the eye runs contrary to empirically determined information on the transport of those drugs.
Geroski and Edelhauser investigated the in vitro passive scleral permeability of numerous compounds. Geroski, D. H. and H. F. Edelhauser, Transscleral drug delivery for posterior segment disease, Adv. Drug. Del. Rev. 52:37-48 (2001). Through their results, Geroski and Edelhauser found that permeability of the compounds was inversely related to molecular weight, with smaller compounds having higher transport rates than larger compounds. Regardless of molecular size, however, the transport rates of all compounds remained relatively high, with small compounds having transport rates on the order of 1×10−5 cm/s, and large compounds having transport rates on the order of 1×10−6 cm/s. Yet despite finding such high permeabilities, Geroski and Edelhauser failed to recognize the reasonable utility of in vivo passive, transscleral drug delivery to achieve therapeutic drug concentrations within the eye.
Thus, the inability to deliver drugs effectively through topical administration must be due to environmental conditions in the drug delivery pathway or within the eye itself that degrade or eliminate the drug. Two particular conditions have been postulated as being responsible for the loss of topically administered drug. Topically administered drugs are exposed directly to lacrimal fluids within the eye, which contain enzymes and proteins that can attack the drug. It is postulated that, once applied, enzymes, which break the drug down from its effective form, attack the drugs. Alternately, the lacrimal proteins can bind with the active form of the drug, thereby inactivating it or preventing its transport. In any case, the environmental conditions in the extrascleral space, within the transport pathways, and within the eye tend to create a harsh environment for the transport and viability of the effective form of the drug.
As mentioned, one reason why conventional topical administration of drugs to the eye has heretofore not achieved effective concentrations of drug in the posterior of the eye is because of the effectiveness of the vasculature in clearing the drug. In order for topically administered compounds to be reach the back of the eye, the drug must pass through several layers of ocular tissues before reaching the vitreous. Several of theses tissues, more specifically the conjunctiva and the choroid, have extensive blood supplies. In addition to delivering nutrients and oxygen to the tissues, these vascular beds are also responsible for removing waste byproducts of metabolism. Further, these vascular beds serve a protective function by removing exogenous and potentially noxious stimuli before they can reach the visual pathways of the eye's interior. These tissues contain the clearing vasculature of the eye, which can shunt the drug from the ocular region to the systemic vasculature, thus not allowing the drug to be exposed to the back of the eye. Combined with enzymatic degradation and protein binding elucidated above, these environmental conditions create a particularly formidable barrier for delivery to the posterior portion of the eye following passive, topical delivery.
As such, it is an object of the present invention to effectively and safely deliver medicament to a posterior retinal portion of an eye, without the potential risks and side effects associated with systemic and injectable delivery methods.
It is another object of the present invention to provide for an enhanced pharmaceutical preparation that improves the effective delivery concentration of a medicament to the intermediate and posterior retinal region.
These and other objects will become apparent to one of ordinary skill in the art given the specification, claims and drawings appended hereto.